Am J Clin Nutr 2006 Calder S1505 1519S

n3 Polyunsaturated fatty acids, inflammation, and inflammatory
diseases13
Philip C Calder
KEY WORDS
Inflammation, monocyte, macrophage, eicosanoid, cytokine, inflammatory disease
INFLAMMATION IN HEALTH AND DISEASE
Inflammation is part of the bodys immediate response to

infection or injury. It is typified by redness, swelling, heat, and
pain. These occur as a result of increased blood flow; increased
permeability across blood capillaries, which permits large molecules (eg, complement, antibodies, and cytokines) to leave the
bloodstream and cross the endothelial wall; and increased movement of leukocytes from the bloodstream into the surrounding
tissue. Inflammation functions to begin the immunologic process
of elimination of invading pathogens and toxins and to repair
damaged tissue. These responses must be ordered and controlled.
The movement of cells into the inflammatory or infected site is
induced by the up-regulation of adhesion molecules such as
intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin on the surface of
endothelial cells, which allows leukocyte binding and subsequent diapedesis. The earliest cells to appear at inflamed sites are
granulocytes, with monocytes, macrophages, and lymphocytes
appearing later. Granulocytes, monocytes, and macrophages are
involved in pathogen killing, in clearing up cellular and tissue
debris, and in tissue repair. The activity of these cells is induced
by certain triggers. One important exogenous trigger is bacterial
endotoxin (also known as lipopolysaccharide), a component of
the cell wall of Gram-negative bacteria, which can directly activate monocytes and macrophages, inducing them to form cytokines, such as tumor necrosis factor (TNF-); interleukin 1
(IL-1), IL-6, and IL-8; eicosanoids, such as prostaglandin (PG)
E2; nitric oxide; matrix metalloproteinases; and other mediators.
Endotoxin also induces adhesion molecule expression on the
surface of endothelial cells and leukocytes.
The cytokines produced by monocytes and macrophages also
serve to regulate the whole-body response to infection and injury
(Figure 1). Thus, inflammation and the inflammatory response
are part of the normal, innate immune response. Inflammatory
mediators also provide a link between innate and acquired immune responses (Figure 1). The actions of inflammatory cytokines, which initiate a cascade of inflammatory mediators, thus
amplifying the initial inflammatory signal, are opposed by antiinflammatory cytokines such as IL-10 and by receptor antagonists such as IL-1 receptor antagonist.
Although inflammation is a normal response, when it occurs in
an uncontrolled or inappropriate manner, excessive damage to
host tissues and disease can ensue. Such uncontrolled or inappropriate inflammatory responses are characterized by hyperexpression of endothelial and leukocyte adhesion molecules,
appearance of soluble forms of adhesion molecules in the circulation, sequestration of leukocytes to sites where they are not
usually found, production of inflammatory mediators, and damage to host tissues (Figure 2). High concentrations of TNF-,
IL-1, and IL-6 are particularly destructive and are implicated in
some of the pathologic responses that occur in endotoxic shock,
in acute respiratory distress syndrome, and in chronic inflammatory diseases such as rheumatoid arthritis and inflammatory
1
From the Institute of Human Nutrition, School of Medicine, University
of Southampton, Southampton, United Kingdom.
2
Presented at the symposium n3 Fatty Acids: Recommendations for
Therapeutics and Prevention, held at the Institute of Human Nutrition,
Columbia University, New York, NY, 21 May 2005.
3
Address reprint requests to PC Calder, Institute of Human Nutrition,
School of Medicine, University of Southampton, Bassett Crescent East,
Southampton SO16 7PX, United Kingdom. E-mail: pcc@soton.ac.uk.
Am J Clin Nutr 2006;83(suppl):1505S19S. Printed in USA. 2006 American Society for Nutrition
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Downloaded from ajcn.nutrition.org by guest on June 30, 2013
ABSTRACT
Inflammation is part of the normal host response to infection and
injury. However, excessive or inappropriate inflammation contributes to a range of acute and chronic human diseases and is characterized by the production of inflammatory cytokines, arachidonic
acid derived eicosanoids (prostaglandins, thromboxanes, leukotrienes, and other oxidized derivatives), other inflammatory agents (eg,
reactive oxygen species), and adhesion molecules. At sufficiently
high intakes, long-chain n3 polyunsaturated fatty acids (PUFAs),
as found in oily fish and fish oils, decrease the production of inflammatory eicosanoids, cytokines, and reactive oxygen species and the
expression of adhesion molecules. Long-chain n3 PUFAs act both
directly (eg, by replacing arachidonic acid as an eicosanoid substrate
and inhibiting arachidonic acid metabolism) and indirectly (eg, by
altering the expression of inflammatory genes through effects on
transcription factor activation). Long-chain n3 PUFAs also give
rise to a family of antiinflammatory mediators termed resolvins.
Thus, n3 PUFAs are potentially potent antiinflammatory agents.
As such, they may be of therapeutic use in a variety of acute and
chronic inflammatory settings. Evidence of their clinical efficacy is
reasonably strong in some settings (eg, in rheumatoid arthritis) but is
weak in others (eg, in inflammatory bowel diseases and asthma).
More, better designed, and larger trials are required to assess the
therapeutic potential of long-chain n3 PUFAs in inflammatory
diseases. The precursor n3 PUFA -linolenic acid does not appear
to exert antiinflammatory effects at achievable intakes.
Am J
Clin Nutr 2006;83(suppl):1505S19S.
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bowel disease. Chronic overproduction of TNF- and IL-1 can

cause adipose tissue and muscle wasting and loss of bone mass
and may account for alterations in body composition and tissue
loss seen in inflammatory diseases and in cancer cachexia. As
well as its clear and obvious association with classic inflammatory diseases, inflammation is now recognized to play an important role in the pathology of other diseases, such as cardiovascular disease and neurodegenerative diseases of aging.
Additionally, the realization that adipose tissue is a source of
inflammatory cytokines has given rise to the notion that obesity,
the metabolic syndrome, and type 2 diabetes have an inflammatory component.
FIGURE 2. Diagrammatic representation of the movement of leukocytes

through the endothelium and the subsequent generation of inflammatory
mediators.
ARACHIDONIC ACIDDERIVED EICOSANOIDS AND

INFLAMMATION
The key link between polyunsaturated fatty acids (PUFAs)

and inflammation is that eicosanoids, which are among the mediators and regulators of inflammation, are generated from 20carbon PUFAs. Because inflammatory cells typically contain a
high proportion of the n6 PUFA arachidonic acid (20:4n6)
and low proportions of other 20-carbon PUFAs, arachidonic acid
is usually the major substrate for eicosanoid synthesis. Eicosanoids, which include PGs, thromboxanes, leukotrienes (LTs),
and other oxidized derivatives, are generated from arachidonic
acid by the metabolic processes summarized in Figure 3. Eicosanoids are involved in modulating the intensity and duration of
inflammatory responses (see references 2 and 3 for reviews),
have cell- and stimulus-specific sources, and frequently have
opposing effects (Table 1). Thus, the overall physiologic (or
pathophysiologic) outcome will depend on the cells present, the
nature of the stimulus, the timing of eicosanoid generation, the
concentrations of different eicosanoids generated, and the sensitivity of the target cells and tissues to the eicosanoids generated.
Recent studies have shown that PGE2 induces cyclooxygenase 2
(COX-2) in fibroblasts cells and so up-regulates its own production (5), induces the production of IL-6 by macrophages (5),
inhibits 5-lipoxygenase (5-LOX) and so decreases production of
the 4-series LTs (6), and induces 15-LOX and so promotes the
formation of lipoxins (6, 7), which have been found to have
antiinflammatory effects (8, 9). Thus, PGE2 possesses both proand antiinflammatory actions (Table 1).
FIGURE 1. The role of inflammatory cells and mediators in regulating the whole-body metabolic and immunologic responses to infection and injury.
Modified from reference 1 with permission from the American Oil Chemists Society.
n3 PUFAs AND INFLAMMATION
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ARACHIDONIC ACID AND INFLAMMATORY

MEDIATOR PRODUCTION
Animal feeding studies have shown a strong positive relation

between the amount of arachidonic acid in inflammatory cells
and the ability of those cells to produce eicosanoids such as PGE2
(10). In turn, the amount of arachidonic acid in inflammatory
cells can be increased by including arachidonic acid in the diet of
rats (10) or by increasing the amount of it in the diet of humans
TABLE 1
Pro- and antiinflammatory effects of prostaglandin E2 (PGE2) and
leukotriene B4 (LTB4)1
PGE2
Proinflammatory
Induces fever
Increases vascular permeability
Increases vasodilatation
Causes pain
Enhances pain caused by other agents
Increases production of IL-6
Antiinflammatory
Inhibits production of TNF and IL-1
Inhibits 5-LOX (decreases 4-series LT production)
Induces 15-LOX (increases lipoxin production)
LTB4
Proinflammatory
Increases vascular permeability
Enhances local blood flow
Chemotactic agent for leukocytes
Induces release of lysosomal enzymes
Induces release of reactive oxygen species by granulocytes
Increases production of TNF, IL-1, and IL-6
1
IL, interleukin; LOX, lipoxygenase; TNF, tumor necrosis factor. Modified from reference 4 with permission from the American Oil Chemists
Society.
(11). The amount of arachidonic acid in inflammatory cells

may also be influenced by dietary intake of its precursor,
linoleic acid (18:2n6), although the range of linoleic acid
intake over which this relation occurs has not been defined for
humans. Increasing linoleic acid intake by 6.5 g/d in humans
who habitually consume 10 15 g/d did not alter the arachidonic acid content of blood mononuclear cells (12). Nevertheless, the role of arachidonic acid as a precursor for the
synthesis of eicosanoids indicates the potential for dietary
n6 PUFAs (linoleic or arachidonic acid) to influence inflammatory processes. This has been little investigated in
humans. Supplementation of the diet of healthy young men
with 1.5 g arachidonic acid/d for 7 wk resulted in a marked
increase in production of PGE2 and LTB4 by endotoxinstimulated mononuclear cells (13). However, production of
TNF-, IL-1, and IL-6 by these cells was not significantly
altered (13). Thus, increased arachidonic acid intake may
result in changes indicative of selectively increased inflammation or inflammatory responses in humans. Supplementation of the diet of healthy elderly subjects with arachidonic
acid [0.7 g/d in addition to a habitual intake of 0.15 g/d (11)]
for 12 wk did not affect endotoxin-stimulated production of
TNF-, IL-1, or IL-6 by mononuclear cells; did not alter
reactive oxygen species (superoxide) production by neutrophils or monocytes; and did not alter plasma soluble
VCAM-1, ICAM-1, or E-selectin concentrations (14). This
lack of effect was despite incorporation of arachidonic acid
into target cells (11). Taken together, these studies suggest
that modestly increased intake of arachidonic acid results in
incorporation of arachidonic acid into cells involved in inflammatory responses (11), but that this does not affect the
production of inflammatory cytokines (13, 14), the generation
of superoxide (14), or the shedding of adhesion molecules
(14), although production of inflammatory eicosanoids is increased (13).
FIGURE 3. Generalized pathway for the conversion of arachidonic acid to eicosanoids. COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid;
HPETE, hydroperoxyeicosatetraenoic acid; LOX, lipoxygenase; LT, leukotriene; PG, prostaglandin; TX, thromboxane.
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FIGURE 4. Relation between tuna oil consumption and the fatty acid
content of human neutrophils. Healthy male volunteers consumed differing
amounts of tuna oil in capsules for 12 wk. Neutrophils were isolated before
and at the end of the intervention period, and the fatty acid composition of
their phospholipids determined. The mean changes in the proportions of
arachidonic acid, docosahexaenoic acid (DHA), and eicosapentaenoic acid
(EPA) were linearly related to the increase in tuna oil consumption (g/d). Data
are from reference 20.
Increased consumption of long-chain n3 PUFAs, such as

eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid
(DHA; 22:6n-3), results in increased proportions of those fatty
acids in inflammatory cell phospholipids (12, 1520). The incorporation of EPA and DHA into human inflammatory cells
occurs in a dose-response fashion and is partly at the expense of
arachidonic acid (Figure 4). Because less substrate is available
for synthesis of eicosanoids from arachidonic acid, fish oil supplementation of the human diet has been shown to result in
decreased production of PGE2 (16, 19, 21, 22), thromboxane B2
(19), LTB4 (15, 17), 5-hydroxyeicosatetraenoic acid (15, 17),
and LTE4 (23) by inflammatory cells. Although these studies
used fish oil, Kelley et al (24) showed that 6 g DHA/d resulted in
decreased production of PGE2 (by 60%) and LTB4 (by 75%) by
endotoxin-stimulated mononuclear cells.
ANTIINFLAMMATORY EFFECTS OF LONG-CHAIN

n3 PUFAs OTHER THAN ALTERED EICOSANOID
PRODUCTION
Although their action in antagonizing arachidonic acid metabolism is a key antiinflammatory effect of n3 PUFAs, these fatty
FIGURE 5. Generalized pathway for the conversion of eicosapentaenoic acid to eicosanoids. COX, cyclooxygenase; HEPE, hydroxyeicosapentaenoic acid;
HPEPE, hydroperoxyeicosapentaenoic acid; LOX, lipoxygenase; LT, leukotriene; PG, prostaglandin; TX, thromboxane.
LONG-CHAIN n3 PUFAs AND INFLAMMATORY

EICOSANOID PRODUCTION
EPA can also act as a substrate for both COX and 5-LOX, giving
rise to eicosanoids with a slightly different structure from those
formed from arachidonic acid (Figure 5). Thus, fish oil supplementation of the human diet has been shown to result in increased production of LTB5, LTE5, and 5-hydroxyeicosapentaenoic acid by
inflammatory cells (15, 17, 23), although generation of PGE3 has
been more difficult to demonstrate (25). The functional significance
of this is that the mediators formed from EPA are believed to be less
potent than those formed from arachidonic acid. For example, LTB5
is 10- to 100-fold less potent as a neutrophil chemotactic agent than
LTB4 (26, 27). Recent studies have compared the effects of PGE2
and PGE3 on production of cytokines by cell lines and by human
cells. Bagga et al (5) reported that PGE3 was a less potent inducer of
COX-2 gene expression in fibroblasts and of IL-6 production by
macrophages. However, PGE2 and PGE3 had equivalent inhibitory
effects on the production of TNF- (28, 29) and IL-1 (29) by
human mononuclear cells stimulated with endotoxin. The reduction
in generation of arachidonic acid derived mediators that accompanies fish oil consumption has led to the idea that fish oil is antiinflammatory (Figure 6).
In addition to long-chain n3 PUFAs modulating the generation of eicosanoids from arachidonic acid and to EPA acting as
a substrate for the generation of alternative eicosanoids, recent
studies have identified a novel group of mediators, termed
E-series resolvins, formed from EPA by COX-2 that appear to
exert antiinflammatory actions (30 32). In addition, DHAderived mediators termed D-series resolvins, docosatrienes and
neuroprotectins, also produced by COX-2, have been identified
and also appear to be antiinflammatory (3335). This is an exciting new area of n3 fatty acids and inflammatory mediators
and the implications for a variety of conditions may be of great
importance. This area was recently reviewed (36, 37).
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dose-response study by Schmidt et al (41) suggests that nearmaximum inhibition of chemotaxis occurs at an intake of 1.3 g
EPADHA/d. A lower intake (0.55 g EPADHA/d) did not
affect monocyte chemotaxis (42). However, Healy et al (20) did
not find an effect of several doses of fish oil providing up to 2.25 g
EPADHA/d on neutrophil chemotaxis. The apparently divergent reports of Schmidt et al (42) and Healy et al (20) could be
explained by the fact that the latter study used a low-EPA, highDHA fish oil such that the highest dose provided 0.58 g EPA/d,
which is less than the amount of EPA provided by the lowest dose
of fish oil used by Schmidt et al. If this is so, then the antichemotactic effects of fish oil might be due to EPA rather than
DHA. No studies have attempted to discriminate the effects of
EPA and DHA on chemotaxis.
acids have several other antiinflammatory effects that might result from altered eicosanoid production or might be independent
of this. For example, studies have shown that, when consumed in
sufficient quantities, dietary fish oil results in decreased leukocyte chemotaxis, decreased production of reactive oxygen species and proinflammatory cytokines, and decreased adhesion
molecule expression (Table 2).
Long-chain n3 PUFAs and adhesion molecule

expression
Cell culture (43 46) and animal feeding studies (47) report
decreased expression of some adhesion molecules on the surface
of monocytes (46), macrophages (47), or endothelial cells (43
45) after exposure to long-chain n3 PUFAs. Supplementing the
diet of healthy humans with fish oil providing 1.5 g
EPADHA/d results in a lower level of expression of ICAM-1
on the surface of blood monocytes stimulated ex vivo with
interferon- (48). Dietary fish oil providing 1.1 g EPADHA/d
was found to decrease circulating concentrations of soluble
VCAM-1 in elderly subjects (49), but it is not clear whether this
represents decreased surface expression of VCAM-1.
Long-chain n3 PUFAs and leukocyte chemotaxis
Long-chain n3 PUFAs and reactive oxygen species

production
Several dietary supplementation studies that used between 3.1

and 14.4 g EPADHA/d have shown a time-dependent decrease
in chemotaxis of human neutrophils and monocytes toward various chemoattractants, including LTB4, bacterial peptides, and
human serum (1517, 38 40). Both the distance of cell migration and the number of cells migrating were decreased. Despite
the high dose of long-chain n3 PUFAs used in these studies, a
Supplementation studies providing 3.1 8.4 g EPADHA/d

have reported 30 55% decreases in the production of reactive
oxygen species (superoxide or hydrogen peroxide) by stimulated
human neutrophils (50 52). Supplementation with 6 g
EPADHA/d was shown to decrease hydrogen peroxide production by human monocytes (53). Studies using lower doses of
long-chain n3 PUFAs (0.552.3 g/d) failed to demonstrate
TABLE 2
Summary of the antiinflammatory effects of long-chain n3 fatty acids1
Antiinflammatory effect
Decreased generation of arachidonic acidderived
eicosanoids (many with inflammatory actions)
Increased generation of EPA-derived eicosanoids
(many with less inflammatory actions than
those produced from arachidonic acid)
Increased generation of EPA and DHA-derived
resolvins (with antiinflammatory actions)
Decreased generation of inflammatory cytokines
(TNF-, IL-1, IL-6, and IL-8)
Decreased expression of adhesion molecules
Decreased leukocyte chemotaxis
Decreased generation of reactive oxygen species
Mechanism likely to be involved

Decreased arachidonic acid in cell membrane phospholipids; inhibition of arachidonic acid
metabolism; decreased induction of COX-2, 5-LOX, and 5-LOX activating protein
Increased content of EPA in cell membrane phospholipids
Increased content of EPA and DHA in cell membrane phospholipids

Decreased activation of NFB (via decreased phosphorylation of IB); activation of PPAR;
altered activity of other transcription factors; differential effects of arachidonic acid vs EPAderived eicosanoids
Decreased activation of NFB (via decreased phosphorylation of IB); altered activity of other
transcription factors
Not clear; perhaps decreased expression of receptors for some chemoattractants
Not clear; perhaps altered membrane composition affecting signaling processes
COX, cyclooxygenase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; IB, inhibitory subunit of NFB; IL, interleukin; LOX, lipoxygenase;
NFB, nuclear factor B; PPAR, peroxisome proliferator-activated receptor; TNF, tumor necrosis factor. Modified from reference 4 with permission from the
American Oil Chemists Society.
1
FIGURE 6. Classic mechanism of the antiinflammatory action of longchain n3 fatty acids. Eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA) decrease the amounts of arachidonic acid available as a substrate
for eicosanoid synthesis and also inhibit the metabolism of arachidonic acid.
COX, cyclooxygenase; LOX, lipoxygenase; LT, leukotriene; PG, prostaglandin; TX, thromboxane.
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CALDER
effects on reactive oxygen species production by either neutrophils (14, 20, 54, 55) or monocytes (14, 42, 54, 55). A study by
Halvorsen et al (56) reported that 3.8 g of either EPA or DHA per
day did not affect production of hydrogen peroxide by human
monocytes. This lack of effect might relate either to the different
stimulus used in this study (Escherichia coli) compared with the
other high dose study with monocytes (latex beads) (53) or to
the fact that 3.8 g long-chain n3 PUFAs/d is below and 6 g/d is
above the threshold that affects hydrogen peroxide production by
monocytes.
Long-chain n3 PUFAs and inflammatory cytokine
production
CLINICAL APPLICATIONS OF THE

ANTIINFLAMMATORY EFFECTS OF LONG-CHAIN
n3 PUFAs
Introductory comments
Inflammation is an overt or covert component of numerous
human conditions and diseases. Although the inflammation may
afflict different body compartments, one common characteristic
of these conditions and diseases is excessive or inappropriate
production of inflammatory mediators, including eicosanoids
FIGURE 7. Inverse relation between the eicosapentaenoic acid (EPA)

content of human mononuclear cells and the production of tumor necrosis
factor (TNF) and interleukin 1 (IL-1). Healthy male volunteers consumed various combinations of sunflower oil, flaxseed oil, and fish oil resulting in various EPA levels in blood mononuclear cells. The mononuclear
cells were isolated and stimulated ex vivo with endotoxin for 24 h. The total
intra- and extracellular accumulation of TNF- and IL-1 was measured by
specific enzyme-linked immunosorbent assays. The concentration of each
inflammatory cytokine was inversely related to the EPA content of the mononuclear cells. Reproduced from reference 19 with permission.
and cytokines. The roles of n6 and n3 PUFAs in shaping and

regulating inflammatory processes and responses suggest that
the balance of these fatty acids might be important in determining
the development and severity of inflammatory diseases. For example, a high intake of n6 PUFAs, especially arachidonic acid,
could contribute to inflammatory processes and so could predispose to or exacerbate inflammatory diseases. Conversely, the
recognition that the long-chain n3 PUFAs have antiinflammatory actions suggests that increasing their intake by patients with
inflammatory diseases, for example, through dietary supplementation, may be of clinical benefit. Possible therapeutic targets for
long-chain n3 PUFAs are listed in Table 3. Supplementation
trials have been conducted for most of these diseases. Those trials
dealing with rheumatoid arthritis, inflammatory bowel diseases
(Crohn disease and ulcerative colitis), and asthma will be reviewed in some detail here. This is because a larger number of
trials have been conducted for these diseases or because the
evidence of benefit is strongest in these diseases.
Cell culture studies show that EPA and DHA can inhibit the
production of IL-1 and TNF- by monocytes (57 60) and the
production of IL-6 and IL-8 by venous endothelial cells (43, 61).
Fish oil feeding decreases the ex vivo production of TNF-,
IL-1, and IL-6 by rodent macrophages (62 64). Supplementation of the diet of healthy humans with fish oil providing 2 g
EPADHA/d was shown to decrease the production of TNF or
IL-1 or IL-6 by mononuclear cells in some studies (16, 19, 21,
65 67). Caughey et al (19) reported a significant inverse correlation between the EPA content of mononuclear cells and the
ability of those cells to produce TNF- and IL-1 in response to
endotoxin (Figure 7). Kelley et al (24) showed that 6 g DHA/d
for 12 wk resulted in decreased production of TNF- (by 20%)
and IL-1 (by 35%) by endotoxin-stimulated mononuclear cells.
Thus, although most studies have used fish oil, it appears that
both EPA (19) and DHA (24) can decrease inflammatory cytokine production. This is confirmed by a study in which persons
with type 2 diabetes were given 4 g EPA or DHA/d for 6 wk (68).
Both EPA and DHA resulted in decreased plasma TNF- concentrations, although DHA was more potent (35% reduction
compared with 20% for EPA). Note, however, that several other
studies failed to show effects of dietary long-chain n3 PUFAs
on the production of inflammatory cytokines in humans. Some of
these studies provided 2 g EPADHA/d (14, 42, 54, 69, 70),
although others provided higher doses (12, 55, 7174). It is not
clear what the reason for these discrepancies in the literature is,
but technical factors are likely to contribute (75). The relative
contributions of EPA and DHA might also be important in determining the effect of fish oil. One other factor that was recently
identified is polymorphisms in genes affecting cytokine production (76). It was found that the effect of dietary fish oil on cytokine production by human mononuclear cells was dependent on
the nature of the 308 TNF- and the 252 TNF- polymorphisms. This study raises the possibility of being able to identify
those who are more likely and those who are less likely to experience specific antiinflammatory effects of fish oil.

TABLE 3
Diseases and conditions with an inflammatory component in which longchain n3 fatty acids might be of benefit1
Disease
(77)
(78)
(78)
(79)
(80)
(80, 81)
(82)
(83)
(84)
(85)
(86)
(87)
(87, 88)
(89, 90)
(90, 91)
(92)
(93)
(94)
(95)
Note: the list is not exhaustive.
Rheumatoid arthritis
Rheumatoid arthritis is a chronic inflammatory disease characterized by joint inflammation that manifests as swelling, pain,
functional impairment, morning stiffness, osteoporosis, and
muscle wasting. Joint lesions are characterized by infiltration of
activated macrophages, T lymphocytes, and plasma cells into the
synovium (the tissue lining the joints) and by proliferation of
synovial cells called synoviocytes. Synovial biopsies from patients with rheumatoid arthritis contain high concentrations of
TNF-, IL-1, IL-6, IL-8, and granulocyte-macrophage colonystimulating factor (GM-CSF), and synovial cells cultured ex vivo
produce TNF-, IL-1, IL-6, IL-8, and GM-CSF for extended
periods of time without additional stimulus (77). COX-2 expression is increased in the synovium of rheumatoid arthritis patients,
and in the joint tissues in rat models of arthritis (96). PGE2, LTB4,
5-hydroxyeicosatetraenoic acid, and platelet-activating factor
are found in the synovial fluid of patients with active rheumatoid
arthritis (97). The efficacy of nonsteroidal antiinflammatory
drugs in rheumatoid arthritis indicates the importance of proinflammatory COX pathway products in the pathophysiology of
the disease. Increased expression of E-selectin, VCAM-1, and
ICAM-1 is found in patients with arthritis, and blocking ICAM-1
or VCAM-1 with antibodies reduces leukocyte infiltration into
the synovium and synovial inflammation in animal models of the
disease (see 98 for references).
Dietary fish oil has been shown to have beneficial effects in
animal models of arthritis. For example, compared with feeding
vegetable oil, feeding mice fish oil delayed the onset (mean: 34 d
compared with 25 d) and reduced the incidence (69% compared
with 93%) and severity (mean peak severity score: 6.7 compared
with 9.8) of type II collagen-induced arthritis (99). Both EPA and
DHA suppressed streptococcal cell wallinduced arthritis in rats,
but EPA was more effective (100).
Several studies have reported antiinflammatory effects of fish

oil in patients with rheumatoid arthritis, such as decreased LTB4
production by neutrophils (101104) and monocytes (103, 105),
decreased IL-1 production by monocytes (106), decreased
plasma IL-1 concentrations (107), decreased serum C-reactive
protein concentrations (101), and normalization of the neutrophil
chemotactic response (108). Several randomized, placebocontrolled, double-blind studies of fish oil in rheumatoid arthritis
have been reported. The characteristics and findings of these
trials are summarized in Table 4. The dose of long-chain n3
PUFAs used in these trials was between 1.6 and 7.1 g/d and
averaged 3.5 g/d. Almost all of these trials showed some benefit of fish oil. Such benefits included reduced duration of morning stiffness, reduced number of tender or swollen joints, reduced
joint pain, reduced time to fatigue, increased grip strength, and
decreased use of nonsteroidal antiinflammatory drugs (Table 4).
Arachidonic acid may contribute to inflammatory processes
by acting as a precursor to eicosanoids known to have a role in
rheumatoid arthritis (77, 78). Additionally, long-chain n3
PUFAs may act as antiinflammatory agents by competing with
arachidonic acid for incorporation into inflammatory cell membranes and for metabolism by enzymes of eicosanoid synthesis.
Thus, it is possible that greater efficacy of n3 PUFAs may be
achieved in rheumatoid arthritis by simultaneously decreasing
n6 PUFA intake, especially that of arachidonic acid. This was
investigated by Adam et al (116). Fish oil, providing 4.2 g EPA
DHA/d, or placebo was given to patients against a background
of a typical Western diet, providing 0.1 0.25 g arachidonic acid/d, or of a diet that restricted the intake of arachidonic acidrich
foods (meat, egg yolk, etc) and that provided 0.025 0.09 g arachidonic acid/d; the latter diet was termed an antiinflammatory
diet. The fish oilinduced decreases in plasma concentrations of
thromboxane A2 and LTB4 and the urinary concentration of PG
metabolites were greater in patients consuming the antiinflammatory diet than in those consuming the Western diet. The reductions in the number of swollen joints, number of tender joints,
patients global assessment, physicians global assessment, and
patients assessment of pain seen with fish oil supplementation
were all also greater for patients consuming the antiinflammatory
diet (116). Nonsteroidal antiinflammatory drug use declined in
patients receiving fish oil against the background of the antiinflammatory diet but not against the background of the Western
diet.
Several reviews of the trials of fish oil in rheumatoid arthritis
have been published (121126), and each concluded that there is
benefit from fish oil. In an editorial commentary discussing the
use of fish oil in rheumatoid arthritis, it was concluded that the
findings of benefit from fish oil in rheumatoid arthritis are robust, dietary fish oil supplements in rheumatoid arthritis have
treatment efficacy, and dietary fish oil supplements should
now be regarded as part of the standard therapy for rheumatoid
arthritis (127). A meta-analysis that included data from 9 trials
published between 1985 and 1992 inclusive and from one unpublished trial concluded that dietary fish oil supplementation
for 3 mo significantly reduces tender joint count (mean difference: 2.9; P 0.001) and morning stiffness (mean difference:
25.9 min; P 0.01) (119). A recent meta-analysis that included data from 10 trials published between 1985 and 2002 was
conducted (120), although this included one study of flaxseed oil,
one study that did not use a control for fish oil, and one study in
which transdermal administration of n3 PUFAs by ultrasound,
Rheumatoid arthritis
Crohn disease
Ulcerative colitis
Lupus
Type 1 diabetes
Type 2 diabetes
Cystic fibrosis
Childhood asthma
Adult asthma
Allergic disease
Psoriasis
Multiple sclerosis
Neurodegenerative disease of aging
Atherosclerosis
Acute cardiovascular events
Obesity
Systemic inflammatory response to surgery, trauma,
and critical illness
Acute respiratory distress syndrome
Cancer cachexia
Reference to the role

of inflammation
1511S
1512S
CALDER
TABLE 4
Overview of placebo-controlled studies using long-chain n3 fatty acids (fish oil) in patients with rheumatoid arthritis1
Duration
(101)
g/d
1.8 1.2
wk
12
(102)
2.7 1.8
14
(103)
(104)
3.2 2.0
2.0 1.3
12
12
(106)
1.7 1.2
24
(106)
3.5 2.4
24
(105)
(109)
2.0 1.3
1.8 1.2
12
24
(107)
(110)
2.0 1.2
2.0 1.2
12
12
(111)
3.8 2.0
16
(112)
(113)
1.7 1.1
1.7 0.4
52
52
(114)
4.6 2.5
2630
(115)
Total 40 mg/kg
(2.23.0)
15
(116)
2.4 1.8
12
(117)
1.4 0.2
( 0.5 -linolenic acid)
in a liquid supplement
16
(118)
Total 3.0
24
Clinical outcomes improved with

long-chain n3 PUFAs
Placebo
Paraffin oil
Number of tender joints; duration of morning

stiffness
Olive oil
Number of tender joints; number of swollen joints;
time to fatigue; physicians global assessment
Olive oil
Number of tender joints; grip strength
Coconut oil
Number of swollen joints; duration of morning
stiffness
Olive oil
grip strength; physicians global assessment
Olive oil
grip strength; physicians global assessment;
duration of morning stiffness
Coconut oil
Number of swollen joints; joint pain index
Mixed oils
Number and severity of tender joints; physicians
global assessment; use of NSAIDs
Mixed oils
Number and severity of tender joints
Vegetable oil
stiffness
Corn oil
Number and severity of tender joints; duration of
morning stiffness
Air
Use of NSAIDs
Olive oil
Physicians pain assessment; patients global
assessment; use of NSAIDs or DMARDs
Corn oil
stiffness; physicians assessment of pain;
physicians global assessment; patients global
assessment
Mixed oils
Number of swollen joints; duration of morning
stiffness; patients assessment of pain; patients
global assessment; physicians global assessment;
health assessment by questionnaire
Corn oil
Number of swollen joints; number of tender joints;
patients global assessment; physicians global
assessment; patients assessment of pain
Liquid supplement None
without added
PUFA
Soybean oil
Duration of morning stiffness; joint pain; time to

onset of fatigue; Ritchies articular index; grip
strength, patients global assessment
Y
Y
Y
N
Y
N
Y
Y
N
Y
N
Y
N2
N2
N
Y
N2
N2
N2
N2
N2
N2
N2
1
AHRQ, Agency for Healthcare Research and Quality; DHA, docosahexaenoic acid; DMARDs, disease-modifying antirheumaric drugs; EPA, eicosapentaenoic acid; NSAIDs, nonsteroidal antiinflammatory drugs.
2
Published too late to be considered.
rather than the oral route, was used. This meta-analysis concluded that fish oil supplementation has no effect on patient
report of pain, swollen joint count, disease activity, or patients
global assessment. However it also stated that in a qualitative
analysis of seven studies that assessed the effect of n3 fatty
acids on anti-inflammatory drug or corticosteroid requirement,
six demonstrated reduced requirement for these drugs and concluded that n3 fatty acids may reduce requirements for corticosteroids. The effects of long-chain n3 PUFAs on tender
joint count was not assessed in reference 120, which reiterated
the findings of the earlier meta-analysis (119) that n3 fatty
acids reduce tender joint counts. Thus, reasonably strong evidence suggests that long-chain-3 PUFAs have some clinical benefits in rheumatoid arthritis.
Inflammatory bowel diseases
Ulcerative colitis and Crohn disease are chronic inflammatory
diseases of the alimentary tract. In ulcerative colitis, the mucosa
of the colon is mainly affected, whereas in Crohn disease, any
part of the alimentary tract from the mouth to the anus can be
affected, although it is usually the ileum and colon. In both
diseases, the intestinal mucosa contains elevated concentrations
Dose of
EPA DHA
Reference
Included in
Included in
Fortin et al
AHRQ
meta-analysis meta-analysis
(119)
(120)
1513S
TABLE 5
Overview of placebo-controlled studies using long-chain n3 fatty acids (fish oil) in patients with inflammatory bowel diseases1
Reference
Disease
Dose of
EPA DHA
Duration
Placebo
wk
12
UC
2.7 1.8
12
Mixed oils
(134)
UC
4.5 1.1
52
Olive oil
(139)
UC
3.2 2.2
16
(141)
UC
24
(142)
CD
2.2 1.5
for 4 wk; then
1.1 0.75
for 20 wk
1.8 0.9
Linoleic acidrich
vegetable oil
Olive oil
52
(143)
UC
Total 5.1
104
Short-chain
fatty acids
Corn oil
(144)
(145)
(146, 147)
CD
UC
UC
2.8 1.5
3.2 2.1
3.2 2.4
52
52
24
Corn oil
Olive oil
Sunflower oil
(148)
UC
Total 5.6
24
Sunflower oil
(149)
CD
1.6 1.1
24
Olive oil
UC & CD
(140)
Olive oil
Decreased sigmoidoscope score; decreased disease activity

in UC (NS); no effect on disease activity in CD
Decreased disease activity; decreased use of
corticosteroids; no effect on sigmoidoscope score; no
effect on gut mucosal histology score
Decreased use of corticosteroids in relapsing patients;
induction of remission in relapsing patients; no effect
on relapse for patients in remission
Decreased gut mucosal histology score; decreased use of
corticosteroids; increased weight gain
No effect on sigmoidoscope score; no effect on gut
mucosal histology score; no effect on relapse; no effect
on rectal bleeding
Y
Y
Y
Y
Increased maintenance in remission; decreased relapse
No effect on gut mucosal histology score; no effect on

dsease activity; no effect on relapse
No effect on relapse
No effect on relapse
Decreased sigmoidoscope score; decreased gut mucosal
histology score; decreased disease activity
Decreased disease activity; decreased sigmoidoscope
score
No effect on disease activity; no effect on body
composition
Y
Y
Y
Y
Y2
N3
AHRQ, Agency for Healthcare Research and Quality; CD, Crohn Disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; UC, ulcerative
colitis.
2
Published in abstract form only.
3
Published too late to be considered.
of inflammatory cytokines and eicosanoids such as LTB4 (128).

The established role of arachidonic acid derived eicosanoids in
the pathophysiology of inflammatory bowel diseases suggests
that a high dietary intake of n6 PUFAs may play a part in
establishing or perpetuating the disease. Indeed, using multivariate analysis, Shoda et al (129) determined that the increased
incidence of Crohn disease in Japan was significantly associated
with an increase in the ratio of n6 to n3 PUFAs in the diet.
They suggested that a diet high in n6 PUFAs relative to n3
PUFAs somehow plays a causal role in the disease, and that an
increase in n3 PUFA intake may be of benefit.
Certainly, dietary fish oil has beneficial effects in animal models of colitis (130, 131). Long-chain n3 PUFAs are incorporated into gut mucosal tissue of patients with inflammatory bowel
disease who supplement their diet with fish oil (132134), and
there are reports that this results in antiinflammatory effects, such
as decreased LTB4 production by neutrophils (134 136) and
colonic mucosa (136, 137), decreased PGE2 and thromboxane B2
production by colonic mucosa (133), and decreased production
of PGE2 by blood mononuclear cells (138). Small open-label or
pilot studies reported clinical benefit of fish oil supplementation
in ulcerative colitis (135, 139).
Several randomized, placebo-controlled, double-blind studies
of fish oil in inflammatory bowel disease have been reported. The
characteristics and findings of these trials are summarized in
Table 5. The dose of long-chain n3 PUFAs used in these trials

was between 2.7 and 5.6 g/d and averaged 4.5 g/d. Some of
these trials indicate benefits of fish oil, including improved clinical score, improved gut mucosal histology, improved sigmoidoscopic score, lower rate of relapse, and decreased use of corticosteroids. One study of special note is that of Belluzzi et al (142)
in which patients with Crohn disease in remission were randomly
assigned to receive placebo or 2.7 g long-chain n3 PUFAs/d
from an enterically coated fish oil preparation for 1 y. The primary outcome was relapse. There was a significant difference in
the proportion of patients who relapsed over 12 mo: 11/39 (28%)
in the fish oil group compared with 27/39 (69%) in the placebo
group (P 0.001). Likewise, there was a significant difference
in the proportion of patients who remained in remission at 12 mo:
59% in the fish oil group compared with 26% in the placebo
group (P 0.003).
Reviews of trials of fish oil in inflammatory bowel diseases
have been published (150 152), and these conclude that there is
some benefit from fish oil. A recent meta-analysis identified 13
studies of fish oil supplementation in inflammatory bowel diseases reporting outcomes related to clinical score, sigmoidoscope score, gut mucosal histology score, induced remission, and
relapse (120). However, there were sufficient data to perform the
meta-analysis only for relapse and only for ulcerative colitis.
Relapse was reported in 5 studies in ulcerative colitis (Table 5),
g/d
1.8 1.3
(132)
Effect of long chain n3 PUFAs on clinical outcomes
Considered in
AHRQ report
(120)
1514S
CALDER
TABLE 6
Overview of placebo-controlled studies using long-chain n3 fatty acids (fish oil) in patients with asthma1
Reference
Dose of
EPA DHA
g/d
(163, 166)
3.2 2.2
(164)
4.0 trace
(167)
3.6 2.4
(168)
Total 1.0
(169)
2.7 1.8
(170)
3.2 2.2
(171)
Not clear (total 3.3)
but n6 to n3
PUFA ratio of
diet capsules 2
(172)
0.72 0.48 ( some
-linolenic acid)2
(173)
1727 mg/kg 7
11.5 mg/kg2
Effects of long chain n3 PUFAs

on clinical outcomes
Included in
Included in
Thien et al AHRQ systematic
meta-analysis
review
(174)
(165)
Duration
Placebo
wk
10
8
10
52
10
24
4
Olive oil
Low n3 PUFA
Olive oil
Not specified
Olive oil
Olive oil
Not clear
Improved PEF
None identified
None identified
Improved FEV1
None identified
None identified
Overall none identified, but FEV1, FVC, PEF, and
FEF2575 in response to methacholine challenge
improved in 40% of patients
Y
Y
Y
Y
Y
Y
N
Y
Y
Y
Y
Y
Y
Y
24
Mixed oils
None identified
40
Olive oil
Decreased asthma symptom scores; decreased bronchial

hyperresponsiveness to acetylcholine challenge
and 3 of these were used for the meta-analysis (134, 143, 145).
Two of these studies reported a higher rate of relapse with fish oil
than with placebo (134, 143), although this was not significant in
either study, whereas one reported no effect (145). The pooled
risk of relapse with long-chain n3 PUFAs relative to placebo
was 1.13 (95% CI: 0.91, 1.57). This meta-analysis concluded that
n3 fatty acids have no effect on relative risk of relapse in
ulcerative colitis and there was a statistically nonsignificant
reduction in requirement for corticosteroids for n3 fatty acids
relative to placebo in two studies (120). A recent study reported
no effect of 2.7 g EPADHA/d for 24 wk on disease activity in
patients with Crohn disease (149).
Thus, despite several favorable studies, the overall view at the
moment must be that only weak evidence exists that long-chain-3
PUFAs have clinical benefits in inflammatory bowel diseases.
However, the apparent ability of long-chain n3 PUFAs to retain
Crohn disease patients in remission (142) is a striking finding.
Asthma
Arachidonic acid derived eicosanoids such as PGD2, LTC4,
LTD4, and LTE4 are produced by the cells that mediate pulmonary inflammation in asthma (eg, mast cells) and are believed to
be major mediators of asthmatic bronchoconstriction. The
4-series LTs have been detected in the blood, bronchoalveolar
lavage fluid, and urine of asthmatics (153). In addition to the role
of arachidonic acid derived eicosanoids as mediators of asthma,
PGE2 is also involved in regulating the development of the T
helper type 2 phenotype of T lymphocytes that predisposes to
allergic inflammation (154) and promotes the formation of immunoglobulin E by B lymphocytes (155). Thus, a hypothesis has
evolved that an increased intake of n6 PUFAs has played a
causal role in increased asthma incidence (156, 157). Epidemiologic data link high n6 PUFA or low n3 PUFA consumption
with childhood asthma (158, 159). Early exposure to long-chain
n3 PUFAs does appear to alter cytokine production by neonatal
T cells (160, 161), although the longer-term clinical impact of
this is not yet clear. Nevertheless, the role of arachidonic acid

derived eicosanoids in asthma has prompted a series of studies
attempting to modify the disease with fish oil treatment. Several
studies have reported antiinflammatory effects of fish oil in patients with asthma, such as decreased 4-series LT production
(162164) and leukocyte chemotaxis (163, 164). Several uncontrolled or open-label trials of fish oil have shown clinical benefit
of fish oil; these are discussed in detail elsewhere (165).
Several randomized, placebo-controlled, double-blind studies
of fish oil in asthma have been reported. The characteristics and
findings of these trials are summarized in Table 6 and are discussed in great detail elsewhere (165, 174). Thien et al (174)
included 8 studies published between 1988 and 2000 in a systematic review. They identified that there was no consistent
effect on forced expiratory volume at one second, peak flow rate,
asthma symptoms, asthma medication use or bronchia hyperreactivity. They conceded that one study in children showed improved peak flow and reduced asthma medication use. A more
recent report covering 26 studies (both randomized placebocontrolled and others) concluded that no definitive conclusion
can yet be drawn regarding the efficacy of n3 fatty acid supplementation as a treatment for asthma in children and adults
(165). However, the studies of Broughton et al (171) and Nagakura et al (173) indicate that there may be subgroups of asthmatic subjects who benefit greatly from long-chain n3 PUFAs.
Clearly, more needs to be done in this area.
IS THERE A ROLE FOR -LINOLENIC ACID IN
MODULATING INFLAMMATION?
Relatively few studies have examined the effect of the

precursor n3 PUFA -linolenic acid on inflammatory outcomes in humans. Caughey et al (19) reported that 13.7 g
-linolenic acid/d for 4 wk resulted in a decrease in production
of TNF- and IL-1 by endotoxin-stimulated mononuclear
cells by 27% and 30%, respectively. By comparison, fish oil
1
AHRQ, Agency for Healthcare Research and Quality; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FEV1, forced expiratory volume at 1 s;
FEF2575, maximum forced expiratory flow; FVC, forced vital capacity; PEF, peak expiratory flow.
2
Study in children.
providing 2.7 g EPADHA/d decreased production of these

cytokines by 70% and 78%, respectively (19). Thus, on a
g/d-basis, long-chain n3 PUFAs are about 9 times as potent
as -linolenic acid with respect to this outcome in healthy
subjects. In contrast with the observations of Caughey et al,
several studies using lower intakes of -linolenic acid (29.5
g/d) did not find effects on neutrophil chemotaxis (20); neutrophil respiratory burst (14, 20, 54); monocyte respiratory
burst (14, 54); TNF-, IL-1, or IL-6 production by
endotoxin-stimulated mononuclear cells (14, 54, 70);
ICAM-1 expression on monocytes (54); or soluble adhesion
molecule concentrations (14). Taken together, these data suggest that increasing -linolenic acid intake to 10 g/d is
required for antiinflammatory effects to be seen. Even then,
the effects will be much more modest than those exerted by
long-chain n3 PUFAs (19).
CONCLUSIONS
The author had no financial or personal interest in any company or organization that might benefit from the content of this review.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
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n3 Polyunsaturated fatty acids, inflammation, and inflammatory

Inflammation is part of the bodys immediate response to

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bowel disease. Chronic overproduction of TNF- and IL-1 can

FIGURE 2. Diagrammatic representation of the movement of leukocytes

ARACHIDONIC ACIDDERIVED EICOSANOIDS AND

The key link between polyunsaturated fatty acids (PUFAs)

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n3 PUFAs AND INFLAMMATION

ARACHIDONIC ACID AND INFLAMMATORY

Animal feeding studies have shown a strong positive relation

(11). The amount of arachidonic acid in inflammatory cells

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Increased consumption of long-chain n3 PUFAs, such as

ANTIINFLAMMATORY EFFECTS OF LONG-CHAIN

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LONG-CHAIN n3 PUFAs AND INFLAMMATORY

n3 PUFAs AND INFLAMMATION

Long-chain n3 PUFAs and adhesion molecule

Long-chain n3 PUFAs and leukocyte chemotaxis

Long-chain n3 PUFAs and reactive oxygen species

Several dietary supplementation studies that used between 3.1

Supplementation studies providing 3.1 8.4 g EPADHA/d

Mechanism likely to be involved

Increased content of EPA and DHA in cell membrane phospholipids

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CLINICAL APPLICATIONS OF THE

FIGURE 7. Inverse relation between the eicosapentaenoic acid (EPA)

and cytokines. The roles of n6 and n3 PUFAs in shaping and

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n3 PUFAs AND INFLAMMATION

Note: the list is not exhaustive.

Several studies have reported antiinflammatory effects of fish

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Reference to the role

Clinical outcomes improved with

Number of tender joints; duration of morning

Duration of morning stiffness; joint pain; time to

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n3 PUFAs AND INFLAMMATION

Decreased sigmoidoscope score; decreased disease activity

Increased maintenance in remission; decreased relapse

No effect on gut mucosal histology score; no effect on

of inflammatory cytokines and eicosanoids such as LTB4 (128).

Table 5. The dose of long-chain n3 PUFAs used in these trials

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Effect of long chain n3 PUFAs on clinical outcomes

Effects of long chain n3 PUFAs

Decreased asthma symptom scores; decreased bronchial

this is not yet clear. Nevertheless, the role of arachidonic acid

Relatively few studies have examined the effect of the

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n3 PUFAs AND INFLAMMATION

providing 2.7 g EPADHA/d decreased production of these

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Inflammation is a component of a range of acute and chronic

PGE3 following derivatization with panacyl bromide by high pressure

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n3 PUFAs AND INFLAMMATION

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factor- and interleukin-6 production by mononuclear cells following

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n3 PUFAs AND INFLAMMATION

of dietary supplementation with fish oil lipids on the airways response